Effectiveness of adeno-associated virus in H9C2 cardiomyoblast and HEK293T cell lines

Diabetes mellitus type 2 (DMT2) is a prevalent disease that affects many people throughout the world leading to issues such as diabetic cardiomyopathy. O-GlcNAcylation dysregulation, caused by increased levels of serum glucose, contributes to the pathophysiology of decreased cardiac function. O-GlcNAcylation modulates cardiac contraction by reacting with either serine or threonine residues. Our goal was to demonstrate the success of infection of adeno-associated virus 9 (AAV9) carrying the gene of alpha-cardiac actin (ACTC) mutated at Thr326. Here we show the expression of the mutant ACTC T326D in H9C2 cardiomyoblasts and HEK293T cell lines. Expression in H9C2 cells was significantly increased compared to WT and control. In addition, expression in HEK293T cells was significantly increased compared to the control. These results are promising in that the ACTC gene carried in AAV9 can be transduced into cells in diabetic mouse model to prevent O-GlcNAcylation and improve cardiac contractility

Automatically generating adaptive logic to balance non-functional tradeoffs during reconfiguration

Increasingly, high-assurance software systems apply selfreconfiguration in order to satisfy changing functional and non-functional requirements. Most self-reconfiguration approaches identify a target system configuration to provide the desired system behavior, then apply a series of reconfiguration instructions to reach the desired target configuration. Collectively, these reconfiguration instructions define an adaptation path. Although multiple satisfying adaptation paths may exist, most self-reconfiguration approaches select adaptation paths based on a single criterion, such as minimizing reconfiguration cost. However, different adaptation paths may represent tradeoffs between reconfiguration costs and other criteria, such as performance and reliability. This paper introduces an evolutionary computationbased approach to automatically evolve adaptation paths that safely transition an executing system from its current configuration to its desired target configuration, while balancing tradeoffs between functional and non-functional requirements. The proposed approach can be applied both at design time to generate suites of adaptation paths, as well as at run time to evolve safe adaptation paths to handle changing system and environmental conditions. We demonstrate the effectiveness of this approach by applying it to the dynamic reconfiguration of a collection of remote data mirrors, with the goal of minimizing reconfiguration costs while maximizing reconfiguration performance and reliability

Dynamic Adaptation of Software-defined Networks for IoT Systems: A Search-based Approach

The concept of Internet of Things (IoT) has led to the development of many complex and critical systems such as smart emergency management systems. IoT-enabled applications typically depend on a communication network for transmitting large volumes of data in unpredictable and changing environments. These networks are prone to congestion when there is a burst in demand, e.g., as an emergency situation is unfolding, and therefore rely on configurable software-defined networks (SDN). In this paper, we propose a dynamic adaptive SDN configuration approach for IoT systems. The approach enables resolving congestion in real time while minimizing network utilization, data transmission delays and adaptation costs. Our approach builds on existing work in dynamic adaptive search-based software engineering (SBSE) to reconfigure an SDN while simultaneously ensuring multiple quality of service criteria. We evaluate our approach on an industrial national emergency management system, which is aimed at detecting disasters and emergencies, and facilitating recovery and rescue operations by providing first responders with a reliable communication infrastructure. Our results indicate that (1) our approach is able to efficiently and effectively adapt an SDN to dynamically resolve congestion, and (2) compared to two baseline data forwarding algorithms that are static and non-adaptive, our approach increases data transmission rate by a factor of at least 3 and decreases data loss by at least 70%

Interspecies DNA acquisition by a naturally competent Acinetobacter baumannii strain

The human pathogen Acinetobacter baumannii possesses high genetic plasticity and frequently acquires antimicrobial resistance genes. Here we investigated the role of natural transformation in these processes. Genomic DNA from different sources, including from carbapenem-resistant Klebsiella pneumoniae strains, was mixed with A. baumannii A118 cells. Selected transformants were analysed by whole-genome sequencing. In addition, bioinformatics analyses and in silico gene flow prediction were also performed to support the experimental results. Transformant strains included some that became resistant to carbapenems or changed their antimicrobial susceptibility profile. Foreign DNA acquisition was confirmed by whole-genome analysis. The acquired DNA most frequently identified corresponded to mobile genetic elements, antimicrobial resistance genes and operons involved in metabolism. Bioinformatics analyses and in silico gene flow prediction showed continued exchange of genetic material between A. baumannii and K. pneumoniae when they share the same habitat. Natural transformation plays an important role in the plasticity of A. baumannii and concomitantly in the emergence of multidrug-resistant strains.Fil: Traglia, German Matias. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Place, Kori. California State University; Estados UnidosFil: Dotto, Cristian Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Fernandez, Jennifer. California State University; Estados UnidosFil: Montaña, Sabrina Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Bahiense, Camila dos Santos. California State University; Estados UnidosFil: Soler Bistue, Alfonso J. C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Iriarte, Andres. Universidad de la Republica. Facultad de Medicina; UruguayFil: Perez, Federico. Louis Stokes Cleveland Department Of Veterans Affairs; Estados UnidosFil: Tolmasky, Marcelo E.. California State University; Estados UnidosFil: Bonomo, Robert A.. Louis Stokes Cleveland Department Of Veterans Affairs; Estados UnidosFil: Melano, Roberto Gustavo. Public Health Ontario Laboratories; CanadáFil: Ramirez, Maria Soledad. California State University; Estados Unido

Brain Network Allostasis after Chronic Alcohol Drinking Is Characterized by Functional Dedifferentiation and Narrowing

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferential connectivity between specific networks. Through this mechanism, occipital cortical areas lost their specific interaction with sensory-insular cortex, striatal, and sensorimotor networks. Second is functional narrowing, which is defined as an increase in neuronal activity and preferential connectivity between specific brain networks. Functional narrowing strengthened the interaction between striatal and prefrontocortical networks, involving the anterior insular, cingulate, orbitofrontal, prelimbic, and infralimbic cortices. Importantly, these two types of alterations persisted after alcohol discontinuation, suggesting that dedifferentiation and functional narrowing rendered persistent network states. Our results support the idea that chronic alcohol drinking, albeit at moderate intoxicating levels, induces an allostatic change in the brain functional connectivity that propagates into early abstinence.Peer reviewe

Open loop amplitudes and causality to all orders and powers from the loop-tree duality

Multiloop scattering amplitudes describing the quantum fluctuations at high-energy scattering processes are the main bottleneck in perturbative quantum field theory. The loop-tree duality is a novel method aimed at overcoming this bottleneck by opening the loop amplitudes into trees and combining them at integrand level with the real-emission matrix elements. In this Letter, we generalize the loop-tree duality to all orders in the perturbative expansion by using the complex Lorentz-covariant prescription of the original one-loop formulation. We introduce a series of mutiloop topologies with arbitrary internal configurations and derive very compact and factorizable expressions of their open-to-trees representation in the loop-tree duality formalism. Furthermore, these expressions are entirely independent at integrand level of the initial assignments of momentum flows in the Feynman representation and remarkably free of noncausal singularities. These properties, that we conjecture to hold to other topologies at all orders, provide integrand representations of scattering amplitudes that exhibit manifest causal singular structures and better numerical stability than in other representations.Comment: Final version to appear in Physical Review Letter

Research Ethics Training in Peru: A Case Study

With the rapidly increasing number of health care professionals seeking international research experience, comes an urgent need for enhanced capacity of host country institutional review boards (IRB) to review research proposals and ensure research activities are both ethical and relevant to the host country customs and needs. A successful combination of distance learning, interactive courses and expert course instructors has been applied in Peru since 2004 through collaborations between the U.S. Naval Medical Research Center Detachment, the University of Washington and the Department of Clinical Bioethics of the National Institutes of Health to provide training in ethical conduct of research to IRB members and researchers from Peru and other Latin American countries. All training activities were conducted under the auspices of the Peruvian National Institute of Health (INS), Ministry of Health. To date, 927 people from 12 different Latin American countries have participated in several of these training activities. In this article we describe our training model

Systematic study of optical potential strengths in reactions on Sn 120 involving strongly bound, weakly bound, and exotic nuclei

We present new experimental angular distributions for the elastic scattering of Li6+Sn120 at three bombarding energies. We include these data in a wide systematic involving the elastic scattering of He4,6,Li7, Be9,B10, and O16,18 projectiles on the same target at energies around the respective Coulomb barriers. Considering this data set, we report on optical model analyses based on the double-folding São Paulo potential. Within this approach, we study the sensitivity of the data fit to different models for the nuclear matter densities and to variations in the optical potential strengths.Fil: Alvarez, M. A. G.. Universidad de Sevilla; EspañaFil: Fernández García, J. P.. Universidad de Sevilla; EspañaFil: León García, J. L.. Universidad de Sevilla; EspañaFil: Rodríguez Gallardo, M.. Universidad de Sevilla; EspañaFil: Gasques, L. R.. Universidade de Sao Paulo; BrasilFil: Chamon, L. C.. Universidade de Sao Paulo; BrasilFil: Zagatto, V. A. B.. Universidade de Sao Paulo; BrasilFil: Lépine Szily, A.. Universidade de Sao Paulo; BrasilFil: Oliveira, J. R. B.. Universidade de Sao Paulo; BrasilFil: Scarduelli, V.. Universidade Federal Fluminense; BrasilFil: Carlson, B. V.. Instituto Tecnologico de Aeronautica.; BrasilFil: Casal, J.. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Arazi, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Torres, D. A.. Universidad Nacional de Colombia; ColombiaFil: Ramirez, F.. Universidad Nacional de Colombia; Colombi

MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders